Appropriate control time constant in relation to characteristics of the baroreflex vascular system in 1/R control of the total artificial heart.

1/R control is a physiological control method of the total artificial heart (TAH) with which long-term survival was obtained with animal experiments. However, 1/R control occasionally diverged in the undulation pump TAH (UPTAH) animal experiment. To improve the control stability of the 1/R control, appropriate control time constant in relation to characteristics of the baroreflex vascular system was investigated with frequency analysis and numerical simulation. In the frequency analysis, data of five goats in which the UPTAH was implanted were analyzed with first Fourier transform technique to examine the vasomotion frequency. The numerical simulation was carried out repeatedly changing baroreflex parameters and control time constant using the elements-expanded Windkessel model. Results of the frequency analysis showed that the 1/R control tended to diverge when very low frequency band that was an indication of the vasomotion frequency was relative high. In numerical simulation, divergence of the 1/R control could be reproduced and the boundary curves between the divergence and convergence of the 1/R control varied depending on the control time constant. These results suggested that the 1/R control tended to be unstable when the TAH recipient had high reflex speed in the baroreflex vascular system. Therefore, the control time constant should be adjusted appropriately with the individual vasomotion frequency.

Principle and basic property of the sequential flow pump.

In the emergency care field, early treatment of acute heart or respiratory failure has been a global concern. In severe cases, patients are frequently required to be on an extracorporeal membrane oxygenator (ECMO) life support. To make the ECMO system more compact and portable, we proposed a sequential flow-type centrifugal pump named the sequential flow pump (SFP). In this study, principle and basic properties of this novel blood pump were examined by computational fluid dynamic (CFD) analysis and an experimental model. In the SFP, fluid is given centrifugal force sequentially twice with a single closed impeller. This sequential pressurization mechanism enables high-pressure output without high impeller speed. To realize easy integration of a blood pump with an artificial lung, the inlet and outlet ports are located at lateral side and center of the pump, respectively, which is the reverse configuration of conventional centrifugal pumps. The computational model was composed for CFD analysis and the experimental model was developed for the experiment of the actual pump. For both models, dimension of the impeller and volute was designed to be equal. In the CFD analysis, the SFP could generate higher performance than the single pressurization model with the same rotational speed of the impeller. Basic property of the experimental model was very similar to that of the computational model. The results showed the possibility that the SFP would be more suitable for the compact ECMO system than conventional centrifugal pumps.

Viscosity-adjusted estimation of pressure head and pump flow with quasi-pulsatile modulation of rotary blood pump for a total artificial heart.

Estimation of pressure and flow has been an important subject for developing implantable artificial hearts. To realize real-time viscosity-adjusted estimation of pressure head and pump flow for a total artificial heart, we propose the table estimation method with quasi-pulsatile modulation of rotary blood pump in which systolic high flow and diastolic low flow phased are generated. The table estimation method utilizes three kinds of tables: viscosity, pressure and flow tables. Viscosity is estimated from the characteristic that differential value in motor speed between systolic and diastolic phases varies depending on viscosity. Potential of this estimation method was investigated using mock circulation system. Glycerin solution diluted with salty water was used to adjust viscosity of fluid. In verification of this method using continuous flow data, fairly good estimation could be possible when differential pulse width modulation (PWM) value of the motor between systolic and diastolic phases was high. In estimation under quasi-pulsatile condition, inertia correction was provided and fairly good estimation was possible when the differential PWM value was high, which was not different from the verification results using continuous flow data. In the experiment of real-time estimation applying moving average method to the estimated viscosity, fair estimation could be possible when the differential PWM value was high, showing that real-time viscosity-adjusted estimation of pressure head and pump flow would be possible with this novel estimation method when the differential PWM value would be set high.

Animal Experiments of the Helical Flow Total Artificial Heart.

Severe cardiac failure patients require a total artificial heart (TAH) to save life. To realize a TAH that can fit a body of small stature and has high performance, high durability, good anatomical fitting, good blood compatibility, and physiological control, we have been developing the helical flow TAH (HFTAH) with two helical flow pumps with hydrodynamic levitation impeller. Animal experiments of the HFTAH were conducted to perform in vivo studies. The HFTAH was implanted in 13 adult female goats weighing 45.0-64.0 kg. After surgery, neither anti-coagulant nor anti-platelet medication was given systemically. The HFTAH was usually driven with a quasi-pulsatile mode. The 1/R control or ΔP control was applied to control the circulation. The ΔP control is a new method using simplified equation of the 1/R control. The HFTAH could be implanted in all goats with good anatomical fitting. Two goats survived for a long time (100 and 68 days). Major causes of termination were device failure and surgical complications. In the device failure, trouble with hydrodynamic bearing was conspicuous. In the two long-term survived goats, experiments were terminated with bearing instability that was probably caused by the suction effect. In these goats, hemolysis occurred on postoperative day 88 and 44, which was considered to be relevant to the bearing trouble. Thrombus was found at the broken right bearing of the 100-day survived goat. However, antithrombogenicity of the pump is expected to be good unless bearing trouble occurs. In two long-term survived goats, the 1/R control or ΔP control worked appropriately to prevent the elevation of right atrial pressure. In both goats, hemodynamic parameters changed with the condition of the animals, liver and kidney functions remained almost normal except when recovering from surgery and during hemolysis, and total protein recovered 2 weeks after surgery. Although instability of the hydrodynamic bearing should be improved, performance of the HFTAH with physiological control could be demonstrated.

Hydrodynamic characteristics of the helical flow pump.

The helical flow pump (HFP) was invented to be an ideal pump for developing the TAH and the helical flow TAH (HFTAH) using two HFPs has been developed. However, since the HFP is quite a new pump, hydrodynamic characteristics inside the pump are not clarified. To analyze hydrodynamic characteristics of the HFP, flow visualization study using the particle image velocimetry and computational fluid dynamics analysis were performed. The experimental and computational models were developed to simulate the left HFP of the HFTAH and distributions of flow velocity vectors, shear stress and pressure inside the pump were examined. In distribution of flow velocity vectors, the vortexes in the vane were observed, which indicated that the HFP has a novel and quite unique working principle in which centrifugal force rotates the fluid in the helical volutes and the fluid is transferred from the inlet to the outlet helical volutes according to the helical structure. In distribution of shear stress, the highest shear stress that was considered to be occurred by the shunt flow across the impeller was found around the entrance of the inlet helical volute. However, it was not so high to cause hemolysis. This shunt flow is thought to be improved by redesigning the inlet and outlet helical volutes. In distribution of pressure, negative pressure was found near the entrance of the inlet helical volute. However, it was not high. Negative pressure is thought to be reduced with an improvement in the design of the impeller or the vane shape.

Concept of left atrial pressure estimation using its pulsatile amplitude in the helical flow total artificial heart.

The total artificial heart (TAH) requires physiological control to respond to the metabolic demand of the body. To date, 1/R control is a single physiological control method that can control venous pressure. To realize an implantable 1/R control system, we are developing a new pressure measuring method using absolute pressure sensor. To find a method for absolute pressure sensor, which went well without calibration, concept of left atrial pressure (LAP) estimation using its pulsatile amplitude was proposed. Its possibility was investigated with two long-term survived goats whose hearts were replaced with the helical flow TAHs. In manual control condition, there existed a positive relation between mean LAP (mLAP) and normalized pulsatile amplitude (NPA). Percent systole revealed not to affect the relationship between mLAP and NPA. Dispersion was observed between different pulse rates. As for cardiac output difference (QLD) that is the difference of flow rate between systolic and diastolic phases, similar results were obtained except in low QLDs. In the 1/R control condition, relatively high correlation between mLAP and NPA could be obtained. In estimation of mLAP using the correlating function of individual goat, fairly good correlation was obtained between measured mLAP and estimated mLAP. Despite that further studies are necessary, it was demonstrated that the concept of the LAP estimation could be possible.

Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin's B-cell lymphoma and is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1',1'-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated whether pyrrolidinium fullerene in combination with the HSP90 inhibitor (geldanamycin; GA) or valproate, potentiated the cytotoxic effects on PEL cells. Compared to treatment with pyrrolidinium fullerene alone, the addition of low-concentration GA or valproate enhanced the cytotoxic activity of pyrrolidinium fullerene. These results indicate that pyrrolidinium fullerene could be used as a novel therapy for the treatment of PEL.

Computational fluid dynamics analysis of the pump parameters in the helical flow pump.

The helical flow pump (HFP) was invented to develop a total artificial heart at the University of Tokyo in 2005. The HFP consists of the multi-vane impeller involving rotor magnets, a motor stator and pump housing having double-helical volutes. To investigate the characteristics of the HFP, computational fluid dynamics analysis was performed. Validation of the computational model was performed with the data of the actual pump. A control computational model in which the vane area corresponded approximately to that of the actual pump was designed for the parametric study. The parametric study was performed varying the vane height, vane width and helical volute pitch. When the vane height was varied from 0.5 to 1.5 times that of the control computational model, the H-Q (pressure head vs. flow) and efficiency curves were translated in parallel with the vane height. When the vane height was two and three times that of the control computational model, the profile of these curves changed. From the results, the best proportion for the vane was considered to be a vane height between 1.5 and 2 times the vane width. The effect of vane width was not very strong compared to that of the vane height. A similar tendency in vane height was observed by varying the helical volute pitch. The best helical volute-pitch size is considered to be between 1.5 and 2 times the vane width. Although further study is necessary to determine the best values for these parameters, the characteristics of the pump parameters in the HFP could be approximately clarified.

Relation between left atrial pressure and the corresponding pulse pressure in the helical flow total artificial heart.

The present control method used in our helical flow total artificial heart (HFTAH) would only need four parameters. Nowadays, gauge pressure sensors are being used to obtain the pressure needed for control parameters. Nevertheless, there are also many following problems such as calibration, maintenance, offset drift and infection due to the skin-penetrative lines for the usage of gauge pressure sensor. Therefore, it is preferable to find another substitutional way instead of the gauge sensor to measure the pressure. In addition, with an eye to completing an implantable HFTAH, we would like to do without any lines through the experiment animal. Therefore, it was confirmed in this study that whether there is a relation between the left atrial pressure (LAP) and its pulse pressure (amplitude). Subsequently the mean value of LAP and its amplitude were quantified. There are two methods used in this study to process the data. Method one, frequency spectrum analysis, is to quantify the signals by getting the absolute value of amplitude for a fixed heartbeat analysis. Method two, by using the synchronous detection method, it is postulated to be more applicable to variant heartbeat data with 1/R control. By the relation of LAP and the pulse pressure acquired in the above two methods, as long as the amplitude of LAP is known by the absolute pressure sensor, it's able to obtain the mean value of LAP (for it suggests a linear relation). Therefore the characteristic could substitute one of the control parameter (that is the LAP), and the other three parameters will be acquired by estimation thus it doesn't need to measure them additionally. Consequently, it is expected that acquiring LAP by absolute pressure sensor for one of the control parameters could attain to an implantable HFTAH.

Emergency Life Support System aiming preprimed oxygenator.

Development have been achieved of a new blood pump for next generation Percutaneous Cardio-Pulmonary Support (PCPS) system and a novel surface coating method for silicone membrane hollow fiber by physical adsorption using a copolymer composed of a 2-Methacryloyloxyethyl phosphorylcholine (MPC) unit and a hydrophobic unit. The new blood pump, named the Troidal Convolution Pump (TCP), is based on the principle of a cascade pump and perfused 5 L/min and 350 mmHg at 2450 rpm. The novel copolymer composed of 30% MPC unit and 3-(methacryloyloxy) propyltris (trimethylsiloxy) silane (MPTSSi) unit (PMMSi30) was the most suitable molecular design on a silicone surface. The PMMSi30 coated surface adsorbed 7.2 % as much protein a non-coated surface adsorbed.

The helical flow total artificial heart: implantation in goats.

To realize a total artificial heart (TAH) with high performance, high durability, good anatomical fitting, and good blood compatibility, the helical flow TAH (HFTAH) has been developed with two helical flow pumps having hydrodynamic levitation impeller. The HFTAH was implanted in goats to investigate its anatomical fitting, blood compatibility, mechanical stability, control stability, and so on. The size of the HFTAH was designed to be 80 mm in diameter and 84 mm wide. The maximum output was 19 L/min against 100 mmHg of pressure head. Eight adult female goats weighting from 45 to 56.3 kg (average 49.7 kg) were used. Under the extracorporeal circulation, natural heart was removed at the atrioventricular groove and the HFTAH was implanted. The HFTAH was driven with a pulsatile mode. The 1/R control was applied when the right atrial pressure recovered. The HFTAH could be implanted with good anatomical fitting in all goats. Two goats survived for more than a week. One goat is ongoing. Other goats did not survive for more than two days with various reasons. In the goats that survived for more than a week, the hydrodynamic bearing was worn and broken, which indicated that the bearing touched to the shaft. The cause was supposed to be the influence of the sucking effect. The potential of the HFTAH could be demonstrated with this study. The stability of the hydrodynamic bearing in a living body, especially the influence of the sucking effect, was considered to be very important and a further study should be necessary.

Pulsatile driving of the helical flow pump.

The helical flow pump (HFP) is newly developed blood pomp for total artificial heart (TAH). HFP can work with lower rotational speed than axial and centrifugal blood pump. It can be seen reasonable feature to generate pulsatile flow because high response performance can be realized. In this article, pulsatility of HFP was evaluated using mock circulation loop. Pulsatile flow was generated by modulating the rotational speed in various amplitude and heart rate. In the experiment, relationship between Pump flow, pump head, rotational speed amplitude, heart rate and power consumption is evaluated. As the result, complete pulsatile flow with mean flow rate of 5 L/min and mean pressure head of 100 mmHg can be obtained at ± 500 rpm with mean rotational speed of 1378 to 1398 rpm in hart rate from 60 to 120. Flow profiles which are non-pulsatile, quasi-pulsatile or complete flow can be adjusted arbitrarily. Therefore, HFP has excellent pulsatility and control flexibility of flow profile.

The helical flow pump with a hydrodynamic levitation impeller.

The helical flow pump (HFP) is a novel rotary blood pump invented for developing a total artificial heart (TAH). The HFP with a hydrodynamic levitation impeller, which consists of a multi-vane impeller involving rotor magnets, stator coils at the core position, and double helical-volute pump housing, was developed. Between the stator and impeller, a hydrodynamic bearing is formed. Since the helical volutes are formed at both sides of the impeller, blood flows with a helical flow pattern inside the pump. The developed HFP showed maximum output of 19 l/min against 100 mmHg of pressure head and 11 % maximum efficiency. The profile of the H-Q (pressure head vs. flow) curve was similar to that of the undulation pump. Hydrodynamic levitation of the impeller was possible with higher than 1,000 rpm rotation speed. The normalized index of the hemolysis ratio of the HFP to centrifugal pump (BPX-80) was from 2.61 to 8.07 depending on the design of the bearing. The HFP was implanted in two goats with a left ventricular bypass method. After surgery, hemolysis occurred in both goats. The hemolysis ceased on postoperative days 14 and 9, respectively. In the first experiment, no thrombus was found in the pump after 203 days of pumping. In the second experiment, a white thrombus was found in the pump after 23 days of pumping. While further research and development are necessary, we are expecting to develop an excellent TAH with the HFP.

Development of normal-suction boundary control method based on inflow cannula pressure waveform for the undulation pump ventricular assist device.

It is desirable to obtain the maximum assist without suction in ventricular assist devices (VADs). However, high driving power of a VAD may cause severe ventricle suction that can induce arrhythmia, hemolysis, and pump damage. In this report, an appropriate VAD driving level that maximizes the assist effect without severe systolic suction was explored. The target driving level was set at the boundary between low driving power without suction and high driving power with frequent suction. In the boundary range, intermittent mild suction may occur. Driving power was regulated by the suction occurrence. The normal-suction boundary control method was evaluated in a female goat implanted with an undulation pump ventricular assist device (UPVAD). The UPVAD was driven in a semipulsatile mode with heartbeat synchronization control. Systolic driving power was adjusted using a normal-suction boundary control method developed for this study. We confirmed that driving power could be maintained in the boundary range. Occurrences of suction were evaluated using the suction ratio. We defined this ratio as the number of suction occurrences divided by the number of heartbeats. The suction ratio decreased by 70% when the normal-suction boundary control method was used.

Results of animal experiments with the fourth model of the undulation pump total artificial heart.

Animal experiments using a total artificial heart in a goat are not easy to perform. The fourth model of the undulation pump total artificial heart (UPTAH4), which was designed to perform a long-term physiological experiment including pulsatile and nonpulsatile TAH operations with a conductance- and arterial pressure-based control method named 1/R control, was implanted in 31 goats weighing 38.5 to 60.4 kg (average of 46.8 kg). The 1/R control is a physiological flow control method of TAH developed with a conductance (1/R: reciprocal of a resistance) parallel circuit model. The survival periods were from 0.1 to 153 days (average of 14.5 days). The causes of termination were postoperative bleeding in eight goats, respiratory failure in five goats, device failure in 14 goats, dissected aneurysm in two goats, and thrombus in one goat. The thrombus case was the longest surviving goat. The respiratory failure tended to occur when the extracorporeal circulation time was prolonged. Autotransfusion was effective for the prolongation of survival time. The left-right balance control and the suction control were performed successfully in all goats. The 1/R control was performed for a long time in five goats that survived for more than 1 month. With three goats that survived for 48, 52, and 53 days mainly with the pulsatile mode, the 1/R control was stable. With a goat that survived for 73 days, the nonpulsatile mode with the 1/R control could be tested for 3 weeks. With the longest surviving goat that was maintained mainly with the pulsatile mode, the 1/R control was unstable, possibly due to the mismatching of the response time of the control system between the computer and the body. However, liver and kidney functions were almost normal, and the total protein level recovered. Further study to stabilize the 1/R control in the UPTAH is necessary.

Automatic calibration of the inlet pressure sensor for the implantable continuous-flow ventricular assist device.

Significant progress in the development of implantable ventricular assist devices using continuous-flow blood pumps has been made recently. However, a control method has not been established. The blood pressure in the inflow cannula (inlet pressure) is one of the candidates for performing an adequate control. This could also provide important information about ventricle sucking. However, no calibration method for an inlet pressure sensor exists. In this study, an automatic calibration algorithm of the inlet pressure sensor from the pressure waveform at the condition of ventricle sucking was proposed. The calibration algorithm was constructed based on the consideration that intrathoracic pressure could be substituted for atmospheric pressure because the lung is open to air. We assumed that the inlet pressure at the releasing point of the sucking would represent the intrathoracic pressure, because the atrial pressure would be low owing to the sucking condition. A special mock circulation system that can reproduce ventricle sucking was developed to validate the calibration algorithm. The calibration algorithm worked well with a maximum SD of 2.1 mmHg for 3-min measurement in the mock circulation system. While the deviation was slightly large for an elaborate calibration, it would still be useful as a primitive calibration. The influence of the respiratory change and other factors as well as the reliability of the calibration value should be investigated with an animal experiment as a next step.

Preliminary study of physiological control for the undulation pump ventricular assist device.

The undulation pump ventricular assist device (UPVAD) is a small implantable ventricular assist device using an undulation pump. The UPVAD can produce pulsatile flow by changing the motor rotation speed of the UPVAD. Because the undulation pump is a volume displacement type pump, the inflow sucking occurs easily. The purpose of this study is to develop a suitable control method for the UPVAD. The UPVAD inflow cannula equipped with an implantable pressure sensor was inserted into the ventricle. Therefore, pressure variation that synchronized with the natural heartbeat and negative pressure spike caused the inflow sucking were observed. By changing the motor rotation speed that responded to the inflow pressure, the UPVAD could synchronize with the natural heartbeat and the UPVAD could generate a co-pulse assist flow. The inflow sucking could be released by reducing the motor rotation speed, if the inflow sucking was detected. The newly developed control method exhibited superior characteristics than existing ones due to high immunity against pressure sensor drift. The assist flow could be increased more than 15% and the inflow sucking occurrence could be decreased with this control method. The UPVAD could generate the suitable assist flow with the developed control method.

Use of in vivo insert molding to form a jellyfish valve leaflet.

We developed an in vivo insert molding technique to form tissue-derived biomaterials into the desired shape, and with sufficient strength and durability, for use in artificial organs. Molds of acrylic resin with inserted velour cloth were implanted under the skin of goats to form a circular leaflet for a jellyfish valve. The valve leaflets were successfully produced in the molds after 17-60 days. Dense connective tissue covered the velour cloth, and loose connective tissue was formed within it. Tissue was radially formed from the hole in the mold. The tissue was simultaneously formed and shrunk. It is necessary to increase the connected portion between the tissue inside and outside the mold so that the tissue can completely cover the inserted materials without shrinkage.

A nonpulsatile total artificial heart with 1/R control.

A total artificial heart (TAH) using continuous flow pumps is promising for size reduction of the device; however, the role of pulsatility in TAHs has been a subject of great debate. Additionally, it is unclear whether, in a nonpulsatile TAH, a physiological control method such as 1/R control can keep the experimental animal in good condition. To realize a nonpulsatile TAH with 1/R control, the artificial valves were removed from undulation pump total artificial hearts (UPTAHs), which can produce both pulsatile and nonpulsatile flows using a single device. The UPTAHs were implanted into 18 goats, and 4 goats survived for more than 1 month. Three weeks of long-term nonpulsatile TAH operation could be tested in the goat that survived for 72 days, and it was proved that 1/R control is possible not only with a pulsatile TAH but also with a nonpulsatile TAH. The general condition of the goat and its organ function did not change on the application of nonpulsatile mode. Cardiac output and arterial pressure changed with the condition of the goat in pulsatile and also in nonpulsatile modes, and the changes seemed almost identical. However, the sucking effect of the atria was very significant in nonpulsatile mode, resulting in hemolysis. Therefore, nonpulsatile TAHs under 1/R control are considered to be inadequate unless some pulsatility can be introduced to avoid fatal sucking effects and to ensure sufficient inflow. During nonpulsatile operation, regular fluctuations were sometimes found in the aortic pressure, and these were caused by the periodic sucking effect in the left atrium that was possibly influenced by respiratory changes.

Fundamental study to develop a fiber-optic gap sensor for a rotary undulation pump.

The rotary undulation pump is believed to be a good candidate for the next-generation artificial heart. Due to its complex movement, it is desirable to magnetically levitate the rotor and dynamically control the gap. In this article, the applicability of a fiber-optic gap sensor to the dynamic position control of the rotor in the rotary undulation pump was investigated. The fiber-optic gap sensor consisted of two plastic-core fibers and a reflection plate. Two 1-mm-diameter optical fibers were aligned parallel: one for source light propagation and the other for reflected light transmission. The basic properties of gap sensors using four different light sources were explored in five media (air, physiologic saline, and blood samples with three different hematocrit levels). The influence of the oxygen saturation level in the blood on sensing was investigated with two types of light sources. It is desirable to use a light source the wavelength of which shows similar absorption coefficients for both oxygenated blood and deoxygenated blood. The effect of the distance between the two fibers on the sensing and range was also investigated. The results indicated that the fiber-optic gap sensor is quite promising for the active control of rotor positioning in the rotary undulation pump.